PANCREAS AND ISLET TRANSPLANTATION

本提案所述工作的总体目标是增加我们的 了解成功胰腺的代谢后果， I型糖尿病患者的胰岛移植，并确定 健康人半胰切除术后的长期代谢结果 捐助者。我们将特别强调长期的后续行动， 成功的胰腺移植和半- 胰腺切除捐赠者，并获得急需的见解， 胰岛移植通常福尔斯下降的原因，尽管使用 用于成功治疗胰腺癌的相同免疫抑制药物方案 移植具体目标是： l）提供连续的、长期的、跨部门的和与时间相关的 胰岛α和β细胞功能的前瞻性评估， I型糖尿病患者的血糖调节和低血糖反调节 糖尿病患者胰腺移植成功。我们假设 胰腺移植将提供长期稳定的 标准化的。 2)确定半胰切除术的长期代谢后果 对胰岛素分泌储备、胰岛素介导的葡萄糖处置以及 葡萄糖介导的葡萄糖处置在具有正常 葡萄糖耐量我们假设胰岛素分泌储备减少 通过胰岛素的代偿性增加进行调整，和/或 外周和/或肝组织的葡萄糖敏感性。 3)确定同种异体胰岛β细胞移植失败 在移植后早期的植入期， 在经典的免疫排斥反应可能发生之前，或者当 血管化移植物的免疫排斥可能是 胰岛衰竭我们假设初始植活失败是一种 主要的和以前未被认识到的部分解释胰岛 失败 4)提供血糖正常和 非胰岛素依赖性自体胰岛移植治疗慢性胰腺炎 患者和I型糖尿病患者的胰岛移植物。我们假设 一旦胰岛移植被证明成功超过一年， 长期稳定的正常化将随之而来。 实现这些目标的研究设计和方法将包括 各种代谢测量，包括葡萄糖和血红蛋白A1 C 水平;测量胰岛素、C肽和胰高血糖素分泌; 放射性同位素膳食研究;低血糖高胰岛素钳夹研究; 葡萄糖增强精氨酸诱导的胰岛素分泌的研究; 正常血糖、高胰岛素钳夹研究，伴和不伴并发 生长抑素输注;和GLUT-4转运蛋白的肌肉水平。 我们预计这些研究将提供深入的代谢评估 糖代谢和反调节低血糖的成功 胰腺移植受者和半胰切除供体 并将为胰岛移植的机制提供新的见解 失败

The overall goal of the work described in this proposal is to increase our understanding of the metabolic consequences of successful pancreas and islet transplantation in Type I diabetic patients, and to ascertain the long term metabolic consequences of hemi-pancreatectomy in healthy human donors. Special emphasis will be given to our long term follow up of recipients of successful pancreas transplantation and of hemi- pancreatectomized donors and to gaining critically needed insights into the reasons why islet transplantation usually falls, despite the use of the identical immunosuppressive drug regimen used for successful pancreas transplantation. The specific aims are: l) To provide serial, long term, cross-sectional and time-related prospective assessments of pancreatic islet alpha and beta cell function, regulation of glycemia, and counterregulation of hypoglycemia in Type I diabetic recipients of successful pancreas transplantation. We hypothesize that pancreas transplantation will provide long-term and stable normalization of glycemia. 2) To determine the long term metabolic consequences of hemipancreatectomy on insulin secretory reserve, insulin-mediated glucose disposal, and glucose-mediated glucose disposal in healthy human donors with normal glucose tolerance. We hypothesize that decreased insulin secretory reserve in donors is adjusted for by compensatory increases in insulin and/or glucose sensitivity in peripheral and/or hepatic tissues. 3) To determine whether failure of allografted pancreatic islet beta cell function occurs early post-transplantation during the engraftment period before classic immunologic rejection is likely, or later when immunorejection of a vascularized graft is the likely explanation for islet failure. We hypothesize that failure of initial engraftment is a major and previously under-recognized part of the explanation for islet failure. 4) To provide long term metabolic assessments of normoglycemic and insulin-independent recipients of islet autografts in chronic pancreatitis patients and islet allografts in Type I diabetic patients. We hypothesize that once islet transplantation has proven successful for over one year, long-term and stable normalization of glycemia will ensue. The research design and methods for achieving these goals will include a variety of metabolic measurements including glucose and hemoglobin A1C levels; measurements of insulin, C-peptide, and glucagon secretion; radioisotopic meal studies; hypoglycemic, hyperinsulinemic clamp studies; studies of glucose potentiation of arginine-induced insulin secretion; euglycemic, hyperinsulineniic clamp studies with and without concurrent somatostatin infusion; and muscle levels of GLUT-4 transporter. We anticipate these studies will provide an in-depth metabolic assessment of glucose metabolism and counterregulation of hypoglycemia in successful recipients of pancreas transplantation and hemi-pancreatectomized donors and will provide new insights into the mechanisms of islet allograft failure.